Targeting surface nucleolin with multivalent HB-19 and related Nucant pseudopeptides results in distinct inhibitory mechanisms depending on the malignant tumor cell type

Autor: Isabelle Nondier, Ara G. Hovanessian, Bernard Krust, Calaiselvy Soundaramourty, Diala El Khoury
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Cancer Research
Cell
Apoptosis
medicine.disease_cause
Cell membrane
Mice
Cell Movement
Cricetinae
Reverse Transcriptase Polymerase Chain Reaction
Wnt signaling pathway
RNA-Binding Proteins
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.anatomical_structure
Matrix Metalloproteinase 9
Oncology
Matrix Metalloproteinase 2
antitumoral action
nucleophosmin
Oligopeptides
Protein Binding
Research Article
Cell type
Immunoblotting
Molecular Sequence Data
HL-60 Cells
CHO Cells
Biology
lcsh:RC254-282
Cricetulus
Cell Line
Tumor
medicine
Cell Adhesion
Genetics
Animals
Humans
anti-inflammatory action
Amino Acid Sequence
Cell adhesion
Cell Proliferation
Dose-Response Relationship
Drug
Cell growth
Cell Membrane
Phosphoproteins
multivalent pseudopeptides
Cancer research
Carcinogenesis
Peptides
Nucleolin
surface nucleolin
nucleolin antagonist peptide
HeLa Cells
Zdroj: BMC Cancer, Vol 11, Iss 1, p 333 (2011)
BMC Cancer
ISSN: 1471-2407
Popis: Background Nucleolin expressed at the cell surface is a binding protein for a variety of ligands implicated in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal RGG domain of nucleolin, the HB-19 pseudopeptide, we recently reported that targeting surface nucleolin with HB-19 suppresses progression of established human breast tumor cells in the athymic nude mice, and delays development of spontaneous melanoma in the RET transgenic mice. Methods By the capacity of HB-19 to bind stably surface nucleolin, we purified and identified nucleolin partners at the cell surface. HB-19 and related multivalent Nucant pseudopeptides, that present pentavalently or hexavalently the tripeptide Lysψ(CH2N)-Pro-Arg, were then used to show that targeting surface nucleolin results in distinct inhibitory mechanisms on breast, prostate, colon carcinoma and leukemia cells. Results Surface nucleolin exists in a 500-kDa protein complex including several other proteins, which we identified by microsequencing as two Wnt related proteins, Ku86 autoantigen, signal recognition particle subunits SRP68/72, the receptor for complement component gC1q-R, and ribosomal proteins S4/S6. Interestingly, some of the surface-nucleolin associated proteins are implicated in cell signaling, tumor cell adhesion, migration, invasion, cell death, autoimmunity, and bacterial infections. Surface nucleolin in the 500-kDa complex is highly stable. Surface nucleolin antagonists, HB-19 and related multivalent Nucant pseudopeptides, exert distinct inhibitory mechanisms depending on the malignant tumor cell type. For example, in epithelial tumor cells they inhibit cell adhesion or spreading and induce reversion of the malignant phenotype (BMC cancer 2010, 10:325) while in leukemia cells they trigger a rapid cell death associated with DNA fragmentation. The fact that these pseudopeptides do not cause cell death in epithelial tumor cells indicates that cell death in leukemia cells is triggered by a specific signaling mechanism, rather than nonspecific cellular injury. Conclusions Our results suggest that targeting surface nucleolin could change the organization of the 500-kDa complex to interfere with the proper functioning of surface nucleolin and the associated proteins, and thus lead to distinct inhibitory mechanisms. Consequently, HB-19 and related Nucant pseudopeptides provide novel therapeutic opportunities in treatment of a wide variety of cancers and related malignancies.
Databáze: OpenAIRE
Externí odkaz: